Perfluoroalkyl and polyfluoroalkyl substances exposure and liver disease: A review

Per- and polyfluoroalkyl substances (PFASs) are widely used in numerous industrial processes and consumer products and are now ubiquitously distributed in the environment, thereby creating multiple routes of human exposure. Their physicochemical properties confer high persistence, bioaccumulation potential, and toxicity, which have raised increasing concern about their long-term impacts on human health. Because of its central role in xenobiotic uptake, metabolism, transport, and excretion, the liver is considered a major target organ of PFAS toxicity. Over the past few years, a growing body of epidemiological, in vivo, and in vitro evidence has linked PFAS exposure to a broad spectrum of hepatic abnormalities, including liver injury, cholestatic liver injury and bile acid dysregulation, metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In addition to legacy long-chain PFASs, short-chain congeners and emerging alternatives such as GenX and 6:2 Cl-PFESA have also shown considerable hepatotoxic potential. This review summarizes current evidence on the contribution of PFAS exposure to liver disease, with particular attention to human relevance and the mechanisms underlying PFAS-induced hepatotoxicity, including oxidative stress, inflammatory activation, disruption of the gut-liver axis and enterohepatic circulation, lipid metabolic reprogramming, and impairment of bile acid homeostasis. Remaining knowledge gaps and future perspectives are also highlighted to support mechanistic understanding and improve PFAS-related liver risk assessment.